NM_001378615.1(CC2D2A):c.517C>T (p.Arg173Ter) AND Meckel syndrome, type 6

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Feb 17, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000049727.12

Allele description [Variation Report for NM_001378615.1(CC2D2A):c.517C>T (p.Arg173Ter)]

NM_001378615.1(CC2D2A):c.517C>T (p.Arg173Ter)

Gene:

CC2D2A:coiled-coil and C2 domain containing 2A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

4p15.32

Genomic location:

Preferred name:

NM_001378615.1(CC2D2A):c.517C>T (p.Arg173Ter)

HGVS:

NC_000004.12:g.15510217C>T
NG_013035.1:g.45352C>T
NM_001080522.2:c.517C>T
NM_001378615.1:c.517C>TMANE SELECT
NM_001378617.1:c.370C>T
NP_001073991.2:p.Arg173Ter
NP_001365544.1:p.Arg173Ter
NP_001365546.1:p.Arg124Ter
LRG_697t1:c.517C>T
LRG_697:g.45352C>T
LRG_697p1:p.Arg173Ter
NC_000004.11:g.15511840C>T

Protein change:

R124*

Links:

dbSNP: rs386833763

NCBI 1000 Genomes Browser:

rs386833763

Molecular consequence:

NM_001080522.2:c.517C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001378615.1:c.517C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001378617.1:c.370C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Meckel syndrome, type 6
Identifiers:: MONDO: MONDO:0012848; MedGen: C2676790; Orphanet: 564; OMIM: 612284

Recent activity

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S41 family peptidase [Azospirillum argentinense]
S41 family peptidase [Azospirillum argentinense]
gi|1634031543|gnl|PRJNA490424|D3093 0|gb|QCN95031.1|

Protein
slc25a20 [Cyprinodon variegatus]
slc25a20 [Cyprinodon variegatus]
Gene ID:107103104

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000082134	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	no assertion criteria provided	probable-pathogenic	unknown	not provided
SCV000593888	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 11, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001521869	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 17, 2020)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19777577, 21866095, 25741868
SCV004101502	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation.

Mougou-Zerelli S, Thomas S, Szenker E, Audollent S, Elkhartoufi N, Babarit C, Romano S, Salomon R, Amiel J, Esculpavit C, Gonzales M, Escudier E, Leheup B, Loget P, Odent S, Roume J, Gérard M, Delezoide AL, Khung S, Patrier S, Cordier MP, Bouvier R, et al.

Hum Mutat. 2009 Nov;30(11):1574-82. doi: 10.1002/humu.21116.

PubMed [citation]

PMID:: 19777577
PMCID:: PMC2783384

Genotype-phenotype correlation in 440 patients with NPHP-related ciliopathies.

Chaki M, Hoefele J, Allen SJ, Ramaswami G, Janssen S, Bergmann C, Heckenlively JR, Otto EA, Hildebrandt F.

Kidney Int. 2011 Dec;80(11):1239-45. doi: 10.1038/ki.2011.284. Epub 2011 Aug 24.

PubMed [citation]

PMID:: 21866095
PMCID:: PMC4037742

See all PubMed Citations (3)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000082134.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

Description

Converted during submission to Likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV000593888.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001521869.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant in the homozygous state has been first reported in a patient with Meckel syndrome [PMID: 19777577, 21866095]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004101502.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The c.517C>T (p.Arg173Ter) variant has been reported previously in homozygous state in patients affected with Meckel syndrome (Chaki M et al, MougouZerelli S et al). The p.Arg173Ter variant is reported with the allele frequency of 0.0008169% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic with a status of criteria provided, single submitter. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. The nucleotide change in CC2D2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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